Blood clots in veins, also known as deep venous thrombosis, affects 1-2 million Americans per year. Deep venous thrombosis can lead to pulmonary embolism, in which the thrombus detaches and travels to the lungs where it can cause fatal cardiopulmonary complications. Pulmonary embolism from deep venous thrombosis is the leading preventable cause of in-hospital death and accounts for greater than 200,000 deaths per year in the U.S. The standard treatment for deep venous thrombosis is immediate anticoagulation which prevents the thrombus from propagating (growing) and subsequently detaching and inducing pulmonary embolism. Anticoagulation, if instituted promptly, is highly effective at preventing pulmonary embolism. Deep venous thrombosis has additional detrimental effects on the vein wall, however, and these changes can cause significant disability and disease. Delayed resolution (healing) of the thrombus results in vein wall and venous valve damage, and eventually can cause post-thrombotic syndrome in 25-75% of patients months to years after a deep venous thrombosis.
Post-thrombotic syndrome can include symptoms of swelling, pain and skin changes up to and including chronic non-healing ulcers of the skin. Post-thrombotic syndrome is due to increased venous pressure in the veins of the leg, and is caused by either loss of the venous valves due to scarring or persistent obstruction of the vein lumen by the thrombus. It is estimated that 2% of total health care costs in the United States are due to treatment of venous leg ulcers, and numerous studies have documented poor quality of life, persistent disability and repeated hospital admission in those patients suffering from venous leg ulcers, which are the most severe manifestation of post-thrombotic syndrome. Approximately 1% of individuals over the age of 65 have a venous leg ulcer per the General Practice Research Database.
These long-term complications of deep venous thrombosis have led to interest in pharmacologic and mechanical therapy to either remove the thrombus or accelerate the body's healing or resolution of the thrombus within the vessel wall. Treatment of deep venous thrombosis within two weeks of onset with thrombolytic therapy or mechanical thrombectomy is possible in some cases, and early clinical trials indicate that early removal of the thrombus results in improved long-term venous function in the leg. Thrombolytic therapy consists of specific enzymatic agents (e.g. tissue plasminogen activator) which cleave the fibrin within the thrombus. Several means of mechanical thrombus removal are also available, including balloon catheter devices (Fogarty catheter), high speed saline irrigation systems (Angiojet) and rotational wire/catheter devices (Trellis). These devices can be combined with pharmacologic thrombolysis as discussed above for greater potential efficacy.
The limitation of both pharmacologic and mechanical thrombectomy is that they are generally are ineffective in patients who present with thrombus of greater than 2 weeks duration. This is due to the natural change in the composition and structure of the thrombus itself over time, where the initial fibrin-rich mass is gradually replaced with a firmer, more fibrotic ingrowth of tissue. This fibrotic tissue is not responsive to the enzymatic action of pharmacologic thrombolysis and is also less amenable to mechanical thrombectomy methods. Thrombolytic therapy has a moderate risk of complications including bleeding from the puncture site, hematoma, rethrombosis and can also have rare but life-threatening complications (e.g. intracranial hemorrhage) which leads to caution in recommending their wide use to treat deep venous thrombosis. Thus, current treatment strategies aimed at deep venous thrombosis are limited to those patients who present for medical care within two weeks of the onset of the thrombosis, which is a subset of all patients with deep venous thrombosis. Both pharmacologic and mechanical thrombolysis are invasive procedures and carry the risk of serious complications.
Another strategy to decrease the detrimental effects of deep venous thrombosis on the vein wall and circulatory system is to accelerate the resolution of the thrombus by the body's own healing mechanisms. The resolution of deep venous thrombosis in patients has been studied with venography (which involves x-rays after injection of contrast material into the vein) as well as non-invasively with duplex ultrasound technology. These studies have demonstrated variable resolution of the obstructive thrombus over time in patients, which is noted as recanalization of the vein by either venography or ultrasound imaging. Those patients who demonstrate rapid resolution of the thrombus generally have improved clinical outcomes and less symptoms of post-thrombotic syndrome than patients with persistent venous obstruction noted by imaging studies.
A similar situation exists in the arterial circulation where thrombus results in the blockage of arteries and decreased flow of oxygenated blood to the downstream tissue. This is compensated for by collateral arteries which increase in size to allow circulation around the blockage. Some arterial thrombi are noted to recanalize over time, potentially allowing circulation through the previously blocked artery. As with deep venous thrombosis, arterial thrombosis can be treated with thrombolytic therapy if detected early, but no specific therapy exists to accelerate resolution of an arterial thrombus to increase the potential chances of recanalization of the artery and restoration of in-line blood flow.
The exact mechanisms of thrombus resolution are not well understood, as resolving deep venous thrombi are rarely if ever removed from patients to allow pathological examination. Thus, our knowledge of the biology and molecular mechanisms of thrombus resolution are largely derived from experimental animal models of deep venous thrombosis, in which pathological examination of the thrombus at different time points reveals a defined cascade of biological events that contribute to the resolution process.
In rodent models of thrombus resolution, the inferior vena cava is surgically ligated to generate a thrombus immediately below the ligature. This thrombus reaches a maximum size in 3-4 days and then undergoes a reduction in size and volume over time. Pathological examination of these thrombi over time demonstrate an early (1-2 days) infiltration of neutrophils into the initially fibrin- and red blood cell-rich thrombus, followed by a subsequent infiltration of macrophages (after 3-4 days) and ingrowth of capillary blood vessels and deposition of collagen. Studies utilizing such rodent models of thrombus resolution have shown an important role for certain genes in the thrombus resolution process, including urokinase-type plasminogen activator and heme oxygenase. Experimental studies designed to improve resolution of deep venous thrombosis with exogenous therapy have shown that gene transfer of the vascular endothelial growth factor (VEGF) gene using an adenovirus injected into the formed thrombus results in improvement in thrombus resolution as measured by thrombus weight at a subsequent time point (Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1753.). It should be noted that injection of experimental thrombi with angiogenic peptide growth factors (VEGF protein rather than an adenovirus) targeted to accelerate thrombus resolution did not result in any improvement in the process of thrombus resolution. (J Vasc Surg. 2004 September;40(3):536-42). Gene therapy with an adenovirus raises serious issues of toxicity and safety of viral vectors and is currently far from clinical use in patients. Treatment of animals with the cytokine macrophage chemotactic factor (MCP-1) does improve experimental thrombus resolution although this agent is not approved for use in humans (J Vasc Surg. 1999; 30: 894-899). Experimental animal studies using the widely available anticoagulant low molecular weight heparin have shown no improvement in the resolution of an established thrombus, which correlates with the clinical data demonstrating that prompt anticoagulation prevents pulmonary embolism but does not alter the resolution of the thrombus in the leg.
In summary, there is currently no specific pharmacologic therapy designed to accelerate resolution of such an established venous thrombosis. The majority of patients with deep venous thrombosis currently do not receive thrombolytic therapy or mechanical thrombectomy as they present after the two week window of time in which this type of therapy is effective at removing the thrombus. Thus, a large population of patients are at substantial risk of long-term development of post-thrombotic syndrome. Post-thrombotic syndrome is a debilitating condition that affects ambulation, the ability to work and overall quality of life. There is no effective treatment for post-thrombotic syndrome once it is established. A pharmacological means of accelerating the resolution of deep venous thrombosis has the potential to improve venous function by either decreasing the obstruction due to thrombus mass or preventing long-term scarring of the venous valves. There is therefore a definite need for pharmacologic or molecular means of accelerating the resolution of deep venous thrombi.